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Table 1 Old studies (from 1962 to 1977) reporting data on polymyxin-induced toxicity in patients without cystic fibrosis

From: Toxicity of polymyxins: a systematic review of the evidence from old and recent studies

  Year [ref] Setting Medication used Number of patients Demographics Dosage of colistin/duration Nephrotoxicity Neurotoxicity Other toxicities
1 1962 [26] Medical wards Colistimethate sodium (IV) 48   Adults: 150 mg q12 h Children: 5 to 10 mg/kg/day. Duration: at least 10 days 12 pts had transient mild elevation of BUN (average increase 14 mg/dl) and returned to normal. 5 pts had prolonged elevation of BUN (average increase 50 mg/dl) and returned to normal 13/48 pts paresthesias; 3/48 pts ataxia 3/48 pts pruritus. No drug fever, hepatic or bone marrow toxicity
2 1963 [19] Medical wards Colistimethate sodium (IM) 1 64 year old male 6.5 mg/kg/day (150 mg q8 h) for 12 days (he received concurrently kanamycin IM for 2 days and after colistin therapy chloramphenicol) BUN increased from normal baseline values to 44 mg/dl (drug was stopped). The BUN continued to rise and then began to return to normal. Postmortem examination of the kidney revealed findings compatible with drug induced nephrotoxicity   Possible hepatotoxicity
3 1963 [66] Medical and surgical wards Colistimethate sodium (IM and topically) 62   Topically: 1% or 2% solution q4h or q12h. Duration (range): 2 to 7 d Intramuscularly (range): 150 to 300 mg/day. Duration (range): 1.5 to 19 d Topically: no side effects Topically: no side effects Intramuscularly: 15/55 pts reported one or more of the following: lethargy, dizziness, nausea, confusion, slurred speech, numbness, paresthesias, pruritus, pain at the injection Topically: no side effects
4 1963 [20] Medical wards Colistimethate sodium (IM) 11   Dosagea: 1.5 MIU q12h for a week and continued for a further week if the pt was improving (2 pts received 2 MIU q8h for 5 days and then 3 MIU q8h) No renal toxicity 2 pts trigeminal paresthesia 1 pt developed follicular rash of the face
     14   Dosage (range): 1 MIU q12h to 1.5 MIU q8 h for 7 or more days    
5 1964 [28] Medical wards Colistimethate sodium (IV) 8 Age (range): 25 to 69 years Dosage: 2 to 2.5 mg/kg q12 h. Duration (range): 8 to 14 days. 4/8 pts fall in creatinine clearance (range: 16.5 to 38 ml/min) and increase in serum creatinine (range: 0.2 to 2 mg/dl) No neurotoxicity No pruritus
6 1964 [21] Children's hospital Colistimethate sodium (IM) 36 new-borns Age (range): 6 hours to 12 days Dosage (range): 2.5 to 5 mg/kg/day in 2 to 4 doses. Total dose (range): 10 to 240 mg (1 new-born (3.3 kg) received 160 mg of colistin (overdosage) in 7 days) 16 pts had renal epithelial tubular cells on urinalyses; 14 pts had urinary protein excretion No neurotoxicity  
7 1964 [22] Medical wards Colistimethate sodium (IM) 1 50 year old male Dosage: 300 mg/day for 5 days, then 200 mg/day for 4 days Urinary retention, rise in blood urea nitrogen Difficulty in breathing, dysphagia, generalized weakness, hallucinations, apnea requiring intubation  
8 1965 [50] Medical wards Colistimethate sodium (IM) 1 66 year old female with azotemia Dosage: 150 mg q 12 h for 8 days. Cumulative dose: 2,550 mg   7th day of colistin: circumoral paresthesias; 8th day: vomiting, difficulty in breathing, moving, speaking, and became apneic; 10th day: grand mal seizures followed by transient right facial and arm weakness  
9 1965 [24] Medical wards Colistimethate sodium (IM) 17 (19 courses) Age (range): 33 to 90 years Total cumulative dose (range): 0.56 gr to 2.4 gr   8 pts dizziness – vertigo (1 pt discontinued), 5 pts oral paresthesias 3 pts pain at site of injection, 3 pts nausea/vomiting, 2 pts pruritus/rash
10 1965 [23] Medical wards Colistimethate sodium (IM) 1   75 mg q12 h   Episodes of ptosis, muscular weakness of the face and of the extremities  
11 1965 [25] Medical wards (renal department) Colistimethate sodium (IM) 25 12 males, 13 females. Age (range): 14 to 66 years. All with impaired renal function Dosage (range): 2 MIU to 4.4 MIU/day. Duration (average): 8.5 days 9/25 pts had an increase in plasma creatinine levels   
12 1966 [46] Medical wards Colistimethate sodium (IM) 1 47 year old female 100 mg q8h   Perioral paresthesia, numbness in the hands, weakness, ataxia, lightheadedness, shortness of breath, apnea Nausea, itching of the face, hands, and arms (no visible rash)
13 1966 [67] Medical wards Colistimethate sodium (IM) 21 All had urinary tract abnormalities or had undergone prostatectomy Dosage: 120 mg (1.5 MIU) q8h for 7 days No constant effect on creatinine clearance was observed   
14 1966 [43] Medical wards Colistimethate sodium (IM) 4 who developed acute renal failure Age (range): 41 to 75 years. All with pre-existing renal disease Dosage: 5 to 6.3 mg/kg/day. Duration (range): 3 to 12 days Acute tubular failure (3 pts acute tubular necrosis, 1 pt recovered) Retrosternal discomfort 1 pt  
15 1966 [48] Medical wards Colistimethate sodium (IM) 1 48 year old female 75 mg q12h (she also received chloramphenicol 500 mg q6h po)   Diplopia and bilateral eye ptosis, weakness of neck flexion, difficulty in raising her arms  
16 1966 [51] Department of anaesthesiology Colistimethate sodium (IM) 1 49 year old female with nephrolithiasis 75 mg q12 h (she also received chloramphenicol 500 mg q4h po and sulfisoxazole 1 g q4h po)   Post-operative apnea  
17 1967 [27] Medical and surgical wards Colistimethate sodium (IV) 23 Males, moderately to severely ill Dosage (range): 1.1 to 5 mg/kg/day q12h for 6 to 7 days (in 2 cases the treatment was discontinued after 2 and 3 days) 6/23 pts renal impairment; 7/23 pts albuminuria 1 pt circumoral paresthesia 5/23 pts mild itching
18 1968 [44] Medical wards Colistimethate sodium (IV) 7 Age (range): 28 to 48 years. 4 females, 3 males; all had terminal and irreversible renal failure 2 to 3 mg/kg (1 dose)   2 pts mild dizziness and instability  
19 1968 [56] Medical wards Colistin sulfate (PO) 93 (48 cases E. coli and 45 cases Shigella spp.)   E. coli : 100,000 IU/kg/day in adults and 150,000 IU/kg/day in children for 7 days Shigella: 200,000 IU/kg/day in adults and 300,000 IU/kg/day in children for 8 to 10 days No toxic symptoms No toxic symptoms 1 pt generalized rash, 1 pt vomiting
20 1968 [49] Medical wards (respiratory care unit) Colistimethate sodium (IM) and Polymyxin B (IM or IV) 11 Age (range): 36 to 74 years. 4 females, 7 males; all had acute or chronic renal disease Dosage of colistimethate sodium (range): 100 to 400 mg/day. Duration (range): 1 to 29 doses or 1 to 15 days. Dosage of polymyxin B: 50 mg (1 dose) IM (1 pt) and 100 mg (1 dose) IV (1 pt)   All pts at their admission had apnea that recovered in all cases. Paresthesias 2 pts, diplopia 3 pts, difficulty in swallowing 3 pts, ptosis 2 pts, generalized weakness 3 pts, blurring of vision 1 pt, slurred speech 1 pt, lethargy 1 pt, coma 1 pt  
21 1969 [42] Medical wards Colistimethate sodium (IV) 1 14 year old male with acute leukemia Dosage: 5 mg/kg/day for 5 days, then increased to 7 mg/kg/day on day 6, 10 mg/kg/day on day 7, and 17 mg/kg/day on day 9. Duration: 14 days Acute tubular necrosis   
22 1969 [29] Medical wards (pediatrics) Colistimethate sodium (IM) 1 4 year old female with appendicitis Dosage: 30 mg/kg q6h (total dose received 1,050 mg during 42 h Acute renal failure Neuromyal hyperactivity, seizure-like episodes, uncoordination, disorientation, flaccid quadriplegia, respiratory arrest, apnea  
23 1970 [4] Medical and surgical wards Colistimethate sodium (IM) 288 (317 courses)   205 courses received a total of <1 gr, 69 courses 1 to 2 gr, 43 courses > 2 gr. All courses were administered IM q12 h Total: 64/317 courses (renal insufficiency 63 pts, acute tubular necrosis 6 pts, hematuria 1 pt) Total: 23/317 courses (paresthesias 15 pts, respiratory insufficiency and apnea 6 pts, nausea and vomiting 4 pts, dizziness 3 pts, muscular weakness 2 pts, peripheral neuropathy, confusion, psychosis, convulsive seizure 1 pt each) Total allergic reactions: 7/317 (drug fever 3 pts, eosinophilia 2 pts, macular eruption 2 pts, urticarial eruption 1 pt)
24 1970 [68] Medical wards and ICU Colistimethate sodium (aerosol) 20 Age (range): 23 to 81 years Group 1: 50 mg q8h for 7 days. Group 2: 100 mg q8h for 7 days No toxic symptoms 1 pt experienced palpitations and a sensation of chest tightness (treatment was discontinued)  
25 1970 [3] Department of pediatrics Colistimethate sodium (IM) 1 Age: 10 months (male) 15 mg q6 h (2 doses) and then 250 mg (38.5 mg/kg) (3 dose) Acute renal failure No neurotoxicity  
26 1970 [30] ICU, neurosurgical department Colistimethate sodium (IV, IM, and aerosol) 14 Age (range): 31 to 71 years Mean duration: 9.7 days. Dosage: 26 MIU/day: 10 MIU IM, 10 MIU IV, and 6 MIU aerosol In all pts a considerable fall in creatinine clearance and rises in blood urea and serum creatinine levels were observed. 5 pts developed acute tubular necrosis (histological confirmed). In 6 pts renal function returned to normal   
27 1970 [69] Department of renal disease Colistimethate sodium (route of administration not reported) 1 41 year old Duration: 7 days. Dose: 6.3 mg/kg/day Severe oliguric renal failure   
28 1970 [31] Department of pediatrics Colistimethate sodium (IM) 1 3 year old 150 mg q8h (she received 3 injections) No renal toxicity No neurotoxicity  
29 1970 [32] Medical wards (urology department) Colistimethate sodium (IM) 1 33 year old male with a solitary kidney 25 mg q6h for 5 days and 250 mg q6h for 1 day Increase in serum creatinine levels compared to baseline levels (1.1 mg/dl to 3 mg/dl) Returned to approximately normal values after 6 months Muscular weakness, generalized paresthesias, speech disturbances, ptosis, hypotonia, areflexia, ataxia, difficulty in breathing  
30 1971 [47] Department of neurology Colistimethate sodium (IM) 1 70 year old male with myasthenia gravis 150 mg (one injection)   2 hours after the injection: muscular weakness; 30 minutes later he developed respiratory arrest  
31 1971 [70] Department of respiratory diseases Polymyxin B (aerosol) 2 Case 1: 51 year old female. Case 2: 57 year old male Case 1: 15 mg Case 2: 10 mg   Case 1: pruritus, nausea, flashing, dyspnea Case 2: acute respiratory acidosis  
32 1973 [33] Medical wards (Hemodialysis Centre) Colistimethate sodium (IM) 2 Case 1: 16 year old female. Case 2: 23 year old female Case 1: 150 mg q6h 1st day, 150 mg q4h 2nd day (20 mg/kg/day) Case 2: 180, 240, 180, 120 mg in divided doses on 1st, 2nd, 3rd, 4th day, respectively Both pts developed acute renal failure Case 1: neuromuscular blockade that resulted in quadriplegia, apnea, cardiac arrest Case 2: circumoral – acral paresthesias  
33 1974 [71] Medical wards Colistimethate sodium (IM) 1 66 year old male 6 MIU/day for 60 days No renal toxicity Total ophthalmoplegia, flaccid paralysis of both upper limbs, reduced speech fluency, difficulty in finding words, apathy  
34 1977 [34] Department of pediatrics Colistimethate sodium (IM) 1 5 year old male 200,000 IU/kg/day for 8 days Acute oliguric renal failure Muscular weakness, speech disturbances  
  1. a1 mg of colistimethate sodium is approximately equal to 12,500 IU. BUN, blood urea nitrogen; ICU, intensive care unit; IM, intramuscularly; IV, intravenously; MIU, million international units; po, per os; Pt(s), patient(s); ref, reference.